Abstract Tumor suppressor p53 plays a key role in tumor suppression. p53 function is frequently impaired in cancer by mutation or other mechanisms, such as overexpression of negative regulators for p53, which contributes greatly to tumorigenesis. Cancer cells often display increased de novo fatty acid (FA) synthesis, which is critical for continued growth and proliferation of cancer cells. Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cancer death in the United States. Further understanding the molecular mechanisms for colorectal tumorigenesis will provide novel strategies for cancer therapy. To identify novel genes that are critical for CRC development, we performed a large-scale unbiased in vivo RNA interference screen, and identified SUMO-Specific Protease SENP6 as a novel gene critical for colorectal tumorigenesis. Currently, the role and its mechanism of SENP6 in colorectal tumorigenesis are unclear. Our preliminary studies showed that SENP6 is frequently overexpressed in CRC, and its overexpression is associated with poor prognosis in CRC. Our preliminary results further strongly suggest that SENP6 overexpression plays a critical role in promoting tumor growth in CRC through inhibition of p53 function and activation of FA synthesis in CRC cells. Based on our preliminary results, we hypothesize that SENP6 plays an unidentified and critical role in promoting tumorigenesis in CRC through inhibiting p53 function and promoting FA synthesis. The goal of this proposed study is to determine the role of SENP6 in colorectal tumorigenesis and its underlying mechanisms, and furthermore, to test the potential therapeutic intervention targeting CRC with SENP6 overexpression. We will test our hypothesis by following specific aims. Aim 1. To determine the role of SENP6 in colorectal tumorigenesis in mouse models. Aim 2. To determine the mechanisms by which SENP6 promotes colorectal tumorigenesis and the potential application of SENP6 in CRC therapy. Aim 2 has following 2 sub-aims. 2A) To test the hypothesis that SENP6 downregulates p53 to promote colorectal tumorigenesis. 2B) To determine the role and mechanism of SENP6 in FA synthesis in CRC and its contribution to colorectal tumorigenesis. We will further test whether pharmacological reactivation of p53 and inhibition of FA synthesis is a potential therapeutic strategy for CRC with SENP6 overexpression. It is our expectation that this proposed study will reveal the critical role and mechanism of SENP6 in colorectal tumorigenesis, and the results from this study will have the potential to lead to the development of novel targets and strategies for CRC therapy.